Fluid Complications

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Malignant pleural effusion complicates the care of approximately 150,000 people in the United States each year.

Malignant Pleural Effusion

Malignant pleural effusion complicates the care of approximately 150,000 people in the United States each year. The pleural effusion is usually caused by a disturbance of the normal Starling forces regulating reabsorption of fluid in the pleural space, secondary to obstruction of mediastinal lymph nodes draining the parietal pleura. Tumors that metastasize frequently to these nodes (eg, lung cancer, breast cancer, and lymphoma) cause most malignant effusions. It is, therefore, puzzling that small-cell lung cancer infrequently causes effusions. Primary effusion lymphomas caused by human herpesvirus 8 and perhaps Epstein-Barr virus (EBV) are seen in patients with acquired immune deficiency syndrome (AIDS).

Sidebar:Stathopoulos et al from Athens, Greece have provided a model to explain why only some cancers result in malignant effusions. They suggest that expression of transcriptional programs leading to higher levels of signaling molecules intrapleurally result in increased permeability. Further interaction with other host cells results in angiogenesis and vascular leakage (Stathopoulos GT, et al: Am J Respir Crit Care Med 186:487–492, 2012). Investigators from Tel Hashomer, Israel provide microstructural support for this theory in a study of pleural biopsies from patients with pleural effusion with and without adenocarcinoma. They demonstrate a striking increase in microvessel density. Capillaries and lymphatics are abnormal, displaying changes in normal antigen expression on endothelial cells and pericytes; these changes correspond to disturbed vessel wall integrity that is consistent with hyperpermeability (Damianovich M, et al: Clin Lung Cancer 14:688–698, 2013). The role of vascular endothelial growth factor in these processes is discussed in this chapter.

Pleural effusion restricts ventilation and causes progressive shortness of breath by compression of lung tissue as well as paradoxical movement of the inverted diaphragm. Pleural deposits of tumor cause pleuritic pain.

Pleural effusions occur more commonly in patients with advanced-stage tumors, who frequently have metastases to the brain, bone, and other organs; physiologic deficits; malnutrition; debilitation; and other comorbidities. Because of these numerous clinical and pathologic variables, it is difficult to perform prospective trials in patients with pleural effusions. For the same reason, it is often difficult to predict a potential treatment outcome or anticipated duration of survival for the specific patient with multiple interrelated clinical problems.

William et al generated survival curves for more than 8,000 patients with non–small-cell lung cancer (NSCLC) with pleural effusion (ie, stage IIIB) from the SEER database and showed that long-term survival is uncommon in this group. The median survival time is approximately 3 months.

Sidebar:Investigators in São Paulo, Brazil studied 22 patients with unilateral malignant pleural effusions following thoracentesis with electrical impedance tomography and described heterogeneous re-ventilation responses. They noted that pleural effusion causes ventilatory asynchrony-sometimes “so extreme that one lung was inflating while the other was deflating,” ie, paradoxical ventilation, immediately reversible with thoracentesis. The authors reported that after thoracentesis, “ipsilateral and contralateral lungs re-aerated immediately and without further re-aeration over the next hour”(Alves SH et al: Ann Am Thorac Soc 11:186–191, 2014).

Morgensztern et al, from Yale University, used Surveillance, Epidemiology, and End Results (SEER) data to identify 57,000 patients with NSCLC; among this group, 9,170 (15.9%) had malignant pleural effusions, including 5,226 with distant metastases and 3,944 without distant metastases. Malignant pleural effusions were associated with larger primary tumors, mediastinal nodal metastasis, and adenocarcinoma. Median survival was better in patients without distant metastasis compared with those who had distant metastasis (5 months vs 3 months, respectively), as were 1- and 2-year survival rates (24.8% vs 12.6% and 11.3 vs 5.4%, respectively).

Diagnosis

The new onset of pleural effusion may herald the presence of a previously undiagnosed malignancy or, more typically, complicate the course of a known tumor. Malignant pleural effusions can lead to an initial diagnosis of cancer in patients. In Nantes, France, pleural effusion was the first symptom of cancer in 41% of 209 patients with malignant pleural effusion; lung cancer in men (42%) and ovarian cancer in women (27%) were most common. It is important to bear in mind that many cancer patients have comorbid illness and that pleural effusion may have another etiology.

Sidebar:A group in Bristol, England did CT pulmonary angiograms on consecutive new patients presenting with unilateral pleural effusion in instances in which there was not an immediately obvious cause. Pulmonary embolism was detected in 9 of 141 patients (6.4%); 8 of these 9 patients also had malignant pleural effusion (Hooper C, et al: Respiration 87:26–31, 2014).

Thoracentesis

Thoracentesis is the first step in management of almost all cases of malignant pleural effusion. Ultrasonography facilitates thoracentesis, reduces the rate of complications such as pneumothorax, and can identify pleural nodules and/or thickening, suggesting malignant etiology, as well as targeting known lesions for pleural biopsy. An adequate specimen should be obtained and sent for lab studies designed to separate benign and malignant effusions, including cell count; determination of glucose, protein, lactate dehydrogenase (LDH), and pH; and appropriate cultures and cytology. Chest pressure and pain during thoracentesis can occur when lung elastance is reduced and pleural pressures are markedly negative. Such pain suggests a “trapped” lung and signals an increased risk of postthoracentesis pulmonary edema.

In circumstances in which it is thought desirable to provide continuing drainage of fluid, Seldinger wire–guided placement of small-bore catheters have largely replaced larger chest tubes. Cafarotti et al described the use of 12-F small-bore catheter placements in more than 1,000 patients, with successful drainage in 93.8% of 324 cases of malignant pleural effusion.

The Light criteria (lactate dehydrogenase [LDH] > 200 U/L; pleural-serum LDH ratio > 0.6; and pleural–serum protein ratio > 0.5) help to categorize pleural effusions as exudates.

The majority of undiagnosed exudates are eventually diagnosed as malignant, whereas < 5% of transudates are shown to be caused by cancer. Transudates may be misclassified as exudates following dehydration or diuresis and if there are erythrocytes (and LDH) in the fluid. Brain natriuretic protein levels are markedly elevated in effusions secondary to congestive heart failure.

Sarkar et al have introduced a simple bedside test that allows identification of exudative effusion at the time of thoracentesis. They add 10 mL of 30% hydrogen peroxide to 200 mL of pleural effusion. When catalase is present (exudates), the effusion foams. None of 32 transudates produced foam, whereas all 52 exudates produced profuse bubbles. The test is not accurate if blood contaminates the fluid.

A negative cytology result is not uncommon and does not rule out a malignant etiology. If cytology is negative in an exudative effusion, approximately 25% will have a positive cytology on a second thoracentesis; blind pleural biopsy may increase the yield to nearly 50%. This low diagnostic yield can be improved by CT or ultrasonographic guidance of needle biopsy.

Investigators in Cambridge, England, report that thickening of the pleura > 1 cm, pleural nodularity, and diaphragmatic thickening > 7 mm on either CT (computed tomography) or ultrasonography suggest malignant effusion. On positron emission tomography (PET) scan, a high SUV (standard uptake value) may indicate a malignant pleural effusion. It is important to note that high SUV values may persist for long periods following talc pleurodesis (TP).

Metintas et al reported results of a randomized, controlled trial of medical thoracoscopy vs CT-guided Abrams pleural needle biopsy for diagnosis in patients with malignant pleural effusions. They studied 124 patients with exudative pleural effusions that were not diagnosed by cytologic analysis. Patients were randomized after CT scan to either thoracoscopy and biopsy or CT-guided needle biopsy. CT-guided needle biopsy yielded diagnostic sensitivity of 87.5%, compared with 94.1% in the thoracoscopy group (not statistically significant). Complication rates were low and acceptable with both methods. The authors recommend use of CT-guided needle biopsy for pleural biopsy as the primary method of diagnosis in patients with pleural thickening or lesions observed by CT scan. In patients with pleural fluid without pleural thickening on CT scan and in those who may have benign pleural pathologies other than tuberculosis, the primary method of diagnosis recommended is thoracoscopy. Letovanec et al, from Lausanne, Switzerland, reported on 47 patients with pleural effusion studied with PET/CT, noting that SUV in malignant effusions is higher than in benign effusions (3.7 vs 1.7 g/mL), showing a correlation between malignant effusion and SUV. They conclude that PET/CT may assist in differentiation between malignant vs benign origin of pleural effusion with high specificity in patients with known cancer, specifically NSCLC.

Because it is sometimes difficult to prove the malignant nature of an effusion cytologically, and because thousands of proteins (secretome) and many other nucleic acids, volatile compounds, etc, have been identified in pleural fluid, many molecular tests on pleural fluid have been investigated. Multiple reports measure pleural tumor marker proteins, glycosaminoglycans, cadherins, matrix metalloproteins, cytokines, telomerase, mRNA, exosomes, and serum and pleural DNA methylation patterns, fluorescence in situ hybridization (FISH), proteomics, and many other methods of pleural fluid testing are described. A number of meta-analyses of diagnostic testing have been published, but to date we are unaware of any test or panel of tests that can reliably diagnose malignant effusions with sufficient confidence to allow clinicians to prescribe treatment with cytotoxic agents in the absence of a pathological diagnosis of cancer. Accordingly, biomarker tests and panels have limited utility at present, except perhaps to guide further diagnostic efforts.

Bhattacharya et al, from Kolkata, India, reported on 66 patients with malignant pleural effusion who underwent closed pleural biopsy routinely with diagnostic thoracentesis. Overall, there was 69% positive cytology: 52% on the first examination, 15% on the second, and 1.5% on the third. Closed pleural biopsy identified malignant pleural effusion in 10 additional patients not diagnosed by fluid cytology. There were no major complications.

Thoracoscopy

Thoracoscopic examination performed with the patient under either general or local anesthesia and using rigid or partly flexible thoracoscopes offers a very high sensitivity, specificity, and diagnostic accuracy with a low complication rate. It allows comprehensive visualization of one pleural cavity, coupled with the opportunity to biopsy areas of disease. This method provides a definitive diagnosis and allows the pathologist to suggest possible sites of primary disease based on the histopathology.

Galbis et al from Valencia, Spain prospectively investigated 110 patients who had thoracoscopy for undiagnosed pleural effusions with negative cytologic examination of fluid obtained by thoracentesis. Following thoracoscopy and biopsy, 30% were diagnosed with nonspecific pleuritis, 17% with malignant pleural mesothelioma, 1.8% with pleural tuberculosis, and 48% with pleural carcinoma.

There was no incidence of later development of a malignant pleural effusion following a benign thoracoscopic study in 25 patients at the Lahey Clinic, but Davies et al from the Oxford Pleural Unit report on longer-term follow-up of patients with a diagnosis of nonspecific pleuritis/fibrosis on thoracoscopic pleural biopsy. They retrospectively reviewed 142 patients with a prior medical thoracoscopy and biopsy. Patients were followed until death or for a mean of 21 months. A total of 44 patients were diagnosed with nonspecific pleuritis/fibrosis and 98 patients (69%) had a definitive histological diagnosis. The authors reported that five (12%) patients with nonspecific pleuritis/fibrosis subsequently had a diagnosis of malignant pleural mesothelioma after a mean interval of 9.8 months. Accordingly the false-negative rate of thoracoscopic biopsy for the detection of pleural malignancy was 5%, with a diagnostic sensitivity of 95% and a negative predictive value of 90%. They conclude that “patients with nonspecific pleuritis/fibrosis require careful follow-up.”

Furthermore, thoracoscopic pleural biopsy permits the diagnosis and staging of malignant mesothelioma if it is the cause of the effusion. Thoracoscopy also offers the opportunity for simultaneous treatment. Both talc pleurodesis and intrapleural catheter drainage have shown sustained benefit in palliative management of both malignant pleural effusion and malignant pleural mesothelioma.

Occult malignancy can exist even in the case of a grossly normal pleura at the time of thoracotomy for resection of lung cancer. Multiple studies, particularly in Japan, have investigated the prognostic value of intraoperative pleural lavage specimen cytologic examination. This would appear to be an area in which productive research could be conducted to answer the question of whether prognosis might be improved in these patients through prospective adjuvant interventional trials.

Kaneda et al, from the Mie Chuo Medical Center in Japan, have reported on the value of pleural lavage cytology examined during surgery for primary lung cancer. They studied 3,231 patients retrospectively who had had thoracic washing cytology at the time of surgical resection of lung cancer, and noted that cytology was positive in 4.58% of cases. These patients had significantly worse survival (P = .001) and a higher incidence of recurrent pleural carcinoma. The investigators comment that positive cytologic findings should be treated as “supplemental…to the precise diagnosis of TNM staging.” They suggest scoring positive pleural cytology findings as a new T3 sub-category (PL3).

This would appear to be an area in which productive research could be conducted to answer the question of whether prognosis might be improved in these patients through prospective adjuvant interventional trials.

Sidebar: What should be done when a small malignant effusion or limited pleural metastases are found at the time of thoracotomy for otherwise resectable lung cancer? The presence of even small pleural effusions has been shown to correlate with reduced survival. Small series have described aggressive surgical interventions-including lobectomy or even pneumonectomy combined with pleurectomy and intrapleural chemotherapy-in lung cancer patients who have metastatic pleural nodules, with and without small pleural effusions. Fiorelli conducted a literature review on this subject and concluded that “no current guidelines support surgery over conservative therapy even when combined with postoperative adjuvant chemotherapy or radiation therapy.” (Fiorelli A, Santini M: Interact Cardiovasc Thorac Surg 17:407-412, 2013).

Bronchoscopy

Bronchoscopy may be helpful when an underlying lung cancer is suspected, especially if there is associated hemoptysis, a lung mass, atelectasis, or a massive effusion. It may also be useful when there is a cytologically positive effusion with no obvious primary tumor.

Prognosis

Prognosis of patients with malignant pleural effusion varies by primary tumor. For example, median survival of patients with lung cancer is 3 months, whereas it is 10 months for patients with breast cancer. Median survival is also shorter in patients with encasement atelectasis (3 months).

Sakr retrospectively reviewed prognostic indicators among 421 patients with malignant pleural effusion who underwent medical thoracoscopy. The median survival of patients with malignant pleural effusion was 9.4 months. In univariate analysis, melanoma, age < 60, bloody effusion, extensive pleural adhesions, and widespread pleural nodules correlated with reduced survival, but extent of pleural tumor did not correlate with reduced survival on multivariate analysis. Survival can be predicted with some precision using a LENT prognostic score.

Treatment

Initial treatment: Palliation

Because malignant pleural effusion causes distress and disability and is associated with brief survival, initial management has chiefly been palliative with either drainage of fluid serially over time or obliteration of the pleural space by pleurodesis. Because the specific clinical circumstances may vary markedly in different patients, treatment must be individualized to provide the best palliation for each patient. Generally, there are a variety of methods available for palliative treatment of malignant effusions, and there is little compelling evidence to guide clinicians in the choice of the best methods. Accordingly, treatment decisions must be made with careful reference to the status of the patient and the skills and equipment available in the local community. In general, malignant pleural effusion should be treated aggressively as soon as it is diagnosed. In most cases, effusion will rapidly recur after treatment by thoracentesis or tube thoracostomy alone.

If a malignant pleural effusion is left untreated, a multiloculated effusion may develop or the underlying collapsed lung will become encased by tumor and fibrous tissue in as many as 10% to 30% of cases. Multiloculated effusions are difficult to drain by thoracentesis or chest tube placement. Once encasement atelectasis has occurred, the underlying lung is “trapped” and will no longer reexpand after thoracentesis or tube thoracostomy. Characteristically, the chest x-ray in such cases shows resolution of the pleural effusion after thoracentesis, but the underlying lung remains partially collapsed. This finding is often misinterpreted by the inexperienced clinician as evidence of a pneumothorax, and a chest tube is placed. The air space persists and the lung remains unexpanded, even with high suction and pulmonary physiotherapy. Allowing the chest tube to remain in place can worsen the situation, resulting in bronchopleural fistulization and empyema. In some cases, a trapped lung on an initial chest x-ray will have delayed reexpansion following drainage with a chest tube or small pleural catheter.

Intrapleural alteplase (10–20 mg diluted in 50 to 150 mL of saline) has been used with success in some patients with gelatinous or loculated effusions, with a low incidence of bleeding complications.

Physical techniques. To avoid encasement atelectasis, pleural effusion should be treated definitively at the time of initial diagnosis. Multiple physical techniques have been used to produce adhesions between the parietal and visceral pleurae, obliterate the space, and prevent recurrence. They include open or thoracoscopic pleurectomy, gauze abrasion, or laser pleurodesis. Surgical methods have not been demonstrated to have any advantage over simpler chemical pleurodesis techniques in the treatment of malignant effusions. Gauze abrasion pleurodesis can be easily employed when unresectable lung cancer with associated effusion is found at the time of thoracotomy.

A randomized, prospective study from Ljubljanska, Slovenia, of 87 patients with malignant pleural effusion secondary to breast cancer showed that the thoracoscopic mechanical abrasion pleurodesis was equivalent to talc pleurodesis (TP) in those with normal pleural fluid pH and superior in patients with a low pH.

Chemical agents. Multiple chemical agents have been used.

• Tetracycline-Tetracycline pleurodesis results in a lower incidence of recurrence when compared with tube thoracostomy alone but often causes severe pain. Tetracycline is no longer commercially available in the United States.

• Doxycycline and minocycline-Doxycycline and minocycline are probably equivalent to tetracycline in terms of their efficacy and associated patient discomfort.

• Erythromycin-Erythromycin also causes pleural pain on administration, and in a small series produced a complete response in 79% of patients at 90 days. Recurrence with necessity for re-intervention was seen in 11.8%.

• Bleomycin-Intrapleural bleomycin, at a dose of 60 U, has been shown to be more effective than tetracycline and is not painful, but it is costly. Absorption of the drug can result in systemic toxicity. Combined use of tetracycline and bleomycin has been demonstrated to be more efficacious than use of either drug singly.

• Talc-Talc pleurodesis was first introduced by Norman Bethune in the 1930s. The first use of talc in malignant pleural effusion was by John Chambers in 1958. Talc powder (Sclerosol Intrapleural Aerosol) has demonstrated efficacy in numerous large studies, preventing recurrent effusion in 70% to 92% of cases. Talc is less painful than tetracycline. Cost is minimal, but special sterilization techniques must be mastered by the hospital pharmacy. Talc formulations may have significant differences in the size of particles. Smaller particles may be absorbed and disseminated systemically and may contribute to the increased incidence of adult respiratory distress syndrome (ARDS) or substantial hypoxemia. Gonzalez et al studied the incidence of lung injury following TP with a median dose of talc (Sclerosol) of 6 g. Cases with new infiltrates on a chest x-ray, increased oxygen requirement, and no identifiable trigger other than talc exposure were considered to represent a talc-related lung injury. A total of 12 of 138 patients experienced increased oxygen requirements within 72 hours of the treatment. Four patients (2.8%) had talc-related lung injury.

Talc has also been shown to cause decreases in forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and diffusing capacity over the long term.

Talc can be insufflated in a dry state at the time of thoracoscopy or instilled as a slurry through a chest tube. The dose should be restricted to no more than 5 g. A prospective phase III Intergroup trial of 501 patients randomized to receive thoracoscopic talc vs talc slurry pleurodesis showed similar efficacy in each arm, with increased respiratory complications (14% vs 6%) but less fatigue and higher patient ratings in the insufflation group.

Multiloculated effusions may follow talc use. It is important to ensure that talc does not solidify and form a concretion in the chest tube, thus preventing the drainage of pleural fluid and complete reexpansion of the lung following pleurodesis. Such an event is more likely when small-bore chest tubes are used.

• Pleurodesis technique-With TP, a 24- to 32-French tube has customarily been inserted through a lower intercostal space and placed on underwater seal suction drainage until all fluid is drained and the lung has completely reexpanded. Because severe lung damage can be produced by improper chest tube placement, it is imperative to prove the presence of free fluid by a preliminary needle tap and to enter the pleural space gently with a blunt clamp technique, rather than by blind trocar insertion. If there is any question about the presence of loculated effusion or underlying adhesions, the use of CT or sonography may enhance the safety of the procedure. In the case of large effusions, especially those that have been present for some time, the fluid should be drained slowly to avoid reexpansion pulmonary edema.

Significant complications can occur with both thoracentesis and chest tube thoracostomy. These procedures should not be performed by inexperienced practitioners without training and supervision. Ultrasound guidance is recommended.

Premedications: If doxycycline or talc is to be used, the patient should be premedicated with narcotics. Intrapleural instillation of 20 mL of 1% lidocaine before administration of the chemical agent may help to reduce pain.

Following instillation of the chemical agent, the chest tube should remain clamped for at least 2 hours. If high-volume drainage persists, the treatment can be repeated. The chest tube can be removed after 2 or 3 days if drainage is < 300 mL/d.

Follow-up x-rays at monthly intervals assess the adequacy of treatment and allow early retreatment in case of recurrence.

Sidebar:Arellano-Orden et al, from Sevilla, Spain, studied 227 patients with malignant pleural effusions treated with large particle (50% of particles > 10 nm) vs small particle (< 20% of particles > 10 nm) talc pleurodesis. Death within 7 days occurred in 8 of 107 patients with small-talc pleurodesis vs 1/127 using large-talc pleurodesis. Levels of interleukin, tumor necrosis factor alpha, vascular endothelial growth factor, and thrombin-antithrombin complex were higher in patients with small-talc pleurodesis, and proinflammatory cytokines were higher in patients with greater tumor burden. The authors concluded that small talc particles provoke a strong inflammatory reaction in both the pleural space and serum, associated with a higher rate of early deaths (Arellano-Orden E, et al: Respiration 86:201–209, 2013).

• Alternative approaches-Use of fluid-sclerosing agents and outpatient pleurodesis has been advocated by some investigators and has the potential for reducing hospital stay and treatment cost. Patz performed a prospective, randomized trial of bleomycin vs doxycycline (72% bleomycin vs 79% doxycycline) pleurodesis via a 14-French catheter and found no difference in efficacy. Aglayan, in Istanbul, Turkey, evaluated iodopovidone via either chest tube or a small-bore catheter in 41 patients. Complete and partial successes were observed in 60% and 27%, respectively. Results did not differ by diameter of the tube. (Because of the risk of iodine toxicity with renal failure and seizures, such use of iodopovidone should be limited to 2% solutions and should not be used in patients taking amiodarone or with prolonged use of topical iodine wound treatments.)

Schneider et al reported on 100 patients with tunneled pleural catheters. The mean residence time of the catheter was 70 days. Spontaneous pleurodesis was achieved in 29 patients. The rate of empyema was 4%. The investigators identified three groups that seemed to benefit: (1) patients with the intraoperative finding of a trapped lung in diagnostic video-assisted thoracic surgery (VATS) procedures; (2) patients after repeated thoracentesis or previously failed attempts at pleurodesis; and (3) patients with a limited life span due to underlying disease.

Other approaches that have been utilized include quinacrine, silver nitrate, powdered collagen, and distilled water, as well as various biologic agents, including Corynebacterium parvum, OK-432, tumor necrosis factor, interleukin-2, interferon-α, interferon-β, and interferon-gamma (Actimmune).

Treatment of encasement atelectasis

If encasement atelectasis is found at thoracentesis or thoracoscopy, tube thoracostomy and pleurodesis are futile and contraindicated.

Management options

Surgical decortication. Surgical decortication has been advocated for this problem. This potentially dangerous procedure may result in severe complications, however, such as bronchopleural fistula and empyema. In carefully selected cases with early multiloculated malignant effusion, gentle thoracoscopic debridement can restore a single cavity and allow effective pleural drainage or TP.

Pleuroperitoneal shunts. The Royal Brompton Hospital, London, group reported experience with pleuroperitoneal shunts in 160 patients with malignant pleural effusion and a trapped lung. Effective palliation was achieved in 95% of patients; 15% of patients required shunt revisions for complications.

Intermittent thoracentesis. Intermittent thoracentesis, as needed to relieve symptoms, may be the best option in patients with a short anticipated survival time.

Catheter drainage. Another option is to insert a tunneled, small-bore, cuffed, silicone catheter (PleurX pleural catheter, Denver Biomaterials, Inc., Denver, Colorado) into the pleural cavity. The patient or family members may then drain fluid, using vacuum bottles, whenever recurrent effusion causes symptoms. Bard manufactures an indwelling catheter gravity drainage system under the trade name Aspira.

Kakuda reported on placement of 61 PleurX pleural catheters in 50 patients with malignant pleural effusions at City of Hope; 34% had lung cancer and 24% had breast cancer. There were no operative deaths. In cases in which the catheter was placed under thoracoscopic control, 27 of 38 patients (68%) had encasement atelectasis visualized. A total of 81% had a good result with control of effusion, with subsequent catheter removal (19%) or intermittent drainage for more than 1 month or until death (62%). A total of 5% of patients had major complications, including empyema and tumor implant. Thoracoscopic techniques are useful in the presence of multiloculated effusion. These catheters can also be inserted using the Seldinger technique with the patient under local anesthesia. Tremblay et al placed 250 PleurX pleural catheters by percutaneous technique in patients under local anesthesia. No further pleural intervention was required during the lives of 90% of the patients. The median overall survival was 144 days, and spontaneous pleurodesis occurred in 43%. Subsequent studies showed that 70% of patients who had full lung expansion had spontaneous pleurodesis, with lifetime control of pleural effusion in 92%. They also reported good results in patients with mesothelioma effusions.

Thornton et al, from Memorial-Sloan Kettering Cancer Center, report on the use of tunneled pleural catheters for treatment of recurrent, symptomatic malignant pleural effusions following failed pleurodesis in 63 patients. Following placement of tunneled catheters, 60 of 63 patients had clinical improvement in dyspnea. After a median of 3 days in the hospital, 90% were discharged with the catheter in place. About one-third (31%) needed intrapleural fibrinolytic therapy for optimum evacuation.

Davies et al, from University Hospital of Wales in Cardiff, reported follow-up at 1 year in an unblinded study of 106 patients from seven hospitals in the United Kingdom who had previously untreated malignant pleural effusions. Patients were randomized to either intrapleural catheters (IPCs) placed on an outpatient basis or chest tube insertion and talc slurry pleurodesis (TP). Dyspnea improved on a visual analog scale in both groups with no significant difference in mean dyspnea (24.7 mm in the intrapleural catheter group; 24.4 mm in the talc group). After 6 months the IPC group had a statistically significant mean difference of 14 mm in the dyspnea score over the talc group. Hospitalization was minimized in the IPC group (median, 0 days compared with 4 days for the talc arm). There was no significant difference in quality of life. Twenty-two percent of patients in the TP arm required further pleural procedures compared with 6% in the IPC group. Adverse events occurred in 21 of 52 patients in the IPC group compared with 7 of 54 in the talc group.

Freeman et al, from Indianapolis, Indiana, performed a propensity-matched comparison of talc poudrage pleurodesis versus tunneled pleural catheters in patients undergoing diagnostic thoracoscopy for malignancy. The group treated with pleural catheters had a significantly shorter hospital stay and interval to initiation of systemic therapy for their malignancy, as well as a lower rate of operative morbidity compared with patients undergoing pleurodesis. The authors also noted that “the rate of freedom from re-intervention equaled that of talc pleurodesis.”

A Point/Counterpoint article in Chest between Pyng Lee, MD, and Richard Light, MD, on the question, “Should thoracoscopic talc pleurodesis be the first choice management for malignant effusion?”serves as a good review of published literature on management of malignant pleural effusions and a spirited debate on the relative risks and benefits of treatment options.

IPCs have been used safely in pediatric patients in two small series. Although there is a small risk of infection in patients with IPCs, it has been shown that such infection is not increased in patients undergoing chemotherapy following catheter placement. There is a small incidence of tumor implantation at the site of the catheter.

Sidebar:Although this chapter does not deal directly with the subject of management of malignant pleural mesothelioma (MPM), the question arises as to what the clinician should do when MPM is identified at the time of diagnostic thoracoscopy and no immediate plan for surgical resection is in place. A review of cases in the Western Australia Mesothelioma registry showed that either talc poudrage or postoperative talc slurry pleurodesis prevented reaccumulation of malignant effusion in approximately 70% of cases. A prospective randomized trial of 175 patients with MPM showed no survival advantage of VATS (video-assisted thoracic surgery) pleurectomy over talc poudrage.

Chemotherapy. If the clinician decides to precede palliative intervention with administration of systemic chemotherapy for the underlying primary malignancy, in tumors such as breast cancer, lymphoma, and small-cell lung cancer, it is important to monitor the patient carefully for recurrent effusion after thoracentesis and to treat such recurrences immediately. A recent spate of published data document the chance of success in clearance of malignant pleural effusions with systemic and intrapleural chemotherapy and/or targeted molecular therapies. Chemotherapy options depend on the cell type of the tumor and the general condition of the patient. Although intrapleural chemotherapy offers the possibility of high-dose local therapy with limited systemic effects, only a few small pilot studies utilizing mitoxantrone, doxorubicin, and hyperthermic cisplatin have been published.

Ang reported longer mean survival (12 months vs 5 months) when systemic chemotherapy was given to 71 patients who initially presented with malignant pleural/pericardial effusions.

Su et al treated 27 patients with NSCLC presenting with a malignant pleural effusion using a regimen of intrapleural cisplatin and gemcitabine (Gemzar) followed by radiotherapy (7,020 cGy in 39 fractions), and completed treatment with IV docetaxel. Only two patients experienced recurrent pleural effusion. The median disease-free and overall survival times were 8 and 16 months, respectively, and 63% of patients were alive at 1 year.

Seto et al reported a single-arm series of 80 patients with previously untreated malignant pleural effusions from NSCLC. The patients had chest tubes placed and were given 25 mg of cisplatin in 500 mL of distilled water intrapleurally. Toxicity was acceptable. Median time of drainage was 4 days. A total of 34% had a complete response and 49% had a partial response, for an overall response rate of 83%. An interesting finding in this study was that the median survival time of all patients was 239 days, longer than typically seen in other series of comparable patients treated with pleurodesis. The authors recommend a phase III study.

Chen et al, in Wenzhou, China, performed a prospective randomized study to evaluate the safety and efficacy of combined intrapleural cisplatin and OK-432 with or without hyperthermic therapy in patients with malignant pleural effusion. A total of 358 patients were randomized. The investigators reported a significantly higher overall response (93% vs 79%) in patients treated with hyperthermic therapy. Median survival time of patients was 8.9 months and 6.2 months, respectively, with versus without hyperthermic therapy, with only mild toxicity reported.

Two important recent studies suggest that tissue obtained from malignant effusions may be useful in implementation of a personalized approach to cancer treatment. Molecular methods can be deployed in situations in which cellular tissue is unavailable or would require risky biopsy techniques. Tsai et al, from the National Taiwan University Hospital, have observed that tumor tissue is often not obtainable or suitable for molecular-based epidermal growth factor receptor (EGFR) mutational analysis in NSCLC. They performed a retrospective evaluation of the role of effusion immunocytochemistry using EGFR mutant–specific antibodies to detect relevant mutations in NSCLC on the cell blocks of malignant pleural effusion from 78 patients with lung adenocarcinoma. They report that their method exhibited a high sensitivity and specificity for mutations and comment that effusion immunocytochemistry provides better prediction of tumor response and progression-free survival with first-line EGFR tyrosine kinase inhibitors (TKIs) than clinical characteristics like sex and smoking status. Patients whose effusion immunocytochemistry showed a reaction to either of the two antibodies had a TKI response rate comparable to those with EGFR mutations assessed by direct sequencing from cell-derived RNA. The investigators suggest that effusion immunocytochemistry could be introduced into clinical practice to help identify NSCLC patients likely to benefit from first-line TKI treatment, especially among those with inadequate tissue for molecular-based EGFR analysis.

Guo et al, from Shandong China, studied the therapeutic effects of and adverse reactions from treatment with erlotinib (Tarceva) for malignant pleural effusions caused by metastatic adenocarcinoma. A total of 128 patients who had failed first-line chemotherapy were divided into mutation and nonmutation groups according to the presence or absence of EGFR mutations. The patients were treated with thoracoscopic TP and oral erlotinib. Short-term and long-term clinical therapeutic effects of erlotinib were evaluated. The EGFR mutation rate of lung adenocarcinoma in pleural metastasis tissue acquired through VATS was higher than that in surgical resection specimens. The authors report a higher complete remission rate in the mutation group compared with the nonmutation group. Overall survival time after erlotinib treatment in patients with EGFR mutations was longer than that in patients without EGFR mutations. The authors comment that “EGFR mutations predict a favorable outcome for malignant pleural effusion of lung carcinoma with Tarceva therapy.” Japanese investigators demonstrated that a multiplex molecular profile identifies genetic abnormalities in cells from approximately 40% of pleural effusions from patients with lung cancer, including EGFR, EML4-ALK, KRAS and EGFR amplification, with a high concordance rate with tissue samples.

Fluid from pleural effusions can also be studied in an attempt to identify mechanisms of acquired resistance to targeted therapies, for example crizotinib for ALK-rearranged lung cancer.

Lombardi et al, from Padova, Italy, treated 18 patients with malignant pleural effusion secondary to ovarian (11) and breast (7) cancers. Following pleural drainage, 120 mg/m2 paclitaxel in normal saline was infused and the pleural catheter clamped and drained 24 hours later. Paclitaxel was measured in blood and pleural fluid at 1, 4, and 24 hours. Chest radiographic surveillance at 1 and 2 months showed an overall response rate of 78%; median overall survival was 8.9 months. Patients with CR had longer survival. Intrapleural paclitaxel concentration was very high (478 mg/L) and declined slowly over 24 hours. Plasma levels were low in most patients (.045 mg/L). The authors concluded that intrapleural paclitaxel is safe and effective.

Sidebar: The role of VEGF and other angiogenic molecules are under active investigation as modulators of pleural hyperpermeability and malignant pleural effusion. A number of studies have demonstrated striking increases in VEGF levels in both blood and pleural fluid. This observation has served as the basis for a number of anecdotal observations and small, early trials of the VEGF antagonist bevacizumab, a humanized monoclonal antibody that binds to VEGF receptors and blocks biological effects of VEGF, given systemically or intrapleurally. VEGF levels in blood and pleural fluid fall in response to treatment and there has been gratifying control of MPE in a substantial percentage of cases treated.

Tamiya et al, in Osaka, Japan, reported on a phase II study of bevacizumab with carboplatin/paclitaxel in 23 patients with nonsquamous, non–small-cell lung cancer with malignant pleural effusion (without prior pleurodesis). Carboplatin/paclitaxel was given only in the first cycle. This was followed by 2 to 6 cycles of chemotherapy with bevacizumab, followed by continued bevacizumab in responding patients. The overall response rate was 60%, and the disease control rate was 87%. The median progression-free survival and overall survival times were 7.1 and 11.7 months, respectively. Plasma vascular endothelial growth factor (VEGF) levels in the effusion were very high at 1,800 pg/mL, and decreased significantly after chemotherapy.

Du et al from Beijing, China conducted a randomized trial in 72 patients with NSCLC and malignant pleural effusion with half of patients treated with intrapleural cisplatin (30 mg) vs intrapleural cisplatin plus bevacizumab (300 mg) at 2-week intervals in addition to 3 cycles of conventional chemotherapy. Control of pleural effusion was greater-83% vs 50%-in the bevacizumab arm. Levels of VEGF messenger RNA were lower in pleural fluid of patients treated with bevacizumab.

Radiation. Radiation therapy may be indicated in some patients with lymphoma but has limited effectiveness in other tumor types, particularly if mediastinal adenopathy is absent.

Chylothorax. Chylothorax (in the absence of trauma) is usually secondary to cancer, most frequently lymphoma. An added element of morbidity is conferred by the loss of protein, calories, and lymphocytes in the draining fluid. Initial treatment is with chest tube drainage and a medium chain triglyceride diet. If chylous drainage persists then consideration of strict nothing-by-mouth status and hyperalimentation may be needed. Although thoracic duct ligation is frequently successful in benign chylothorax, there are few reports of its use for malignant effusions. Chylothorax secondary to lymphoma is usually of low volume and responds to TP in combination with radiotherapy or chemotherapy.

Gross et al, from Sao Paulo, Brazil, reported an overall survival rate of 5.6 months for patients with simultaneous ascites and malignant pleural effusions vs 7.8 months in patients without ascites. They observed that success rates for TP were equal and concluded that concomitant ascites did not influence the effectiveness of palliative surgical management of pleural effusion in patients with malignancies.

Research into quality of life and cost-effectiveness research has advanced in the last few years.

Cost-effectiveness analysis comparing long-term catheter drainage vs TP has not found one approach to be significantly better than the other.

Puri et al, from Washington University at St. Louis, performed a decision analysis to compare repeated thoracentesis, tunneled pleural catheter (TPC), bedside pleurodesis (BP), and thoracoscopic pleurodesis (TP). They studied two scenarios: expected survival of 3 months and 12 months. The incremental cost-effectiveness ratio (ICER) was estimated as least expensive with repeat thoracentesis, in the case of 3-month survival. In comparison, the ICER with intrapleural catheter was $6,450 vs $4,946, with expected survivals of 3 months and 12 months, respectively. Bedside TP (about $11,000) and operative TP (a little over $18,000) were more expensive. The ICER for tunneled pleural catheter over repeat thoracentesis was nearly $50,000. In the case of 12 month–long survival, bedside TP was least expensive (about $13,000) and provided 0.59 quality-adjusted life-years. IPC was approximately $150 more expensive, whereas TP cost $19,000 and repeat thoracentesis was $21,000. They noted that thoracoscopic TP was more effective than bedside TP but that ICER was greater than $250,000. They conclude that IPC treatment is preferable for patients with malignant pleural effusion who have limited survival. Penz et al studied costs in Britain using data from a clinical trial, and found no significant difference in cost between IPC and talc pleurodesis. IPC treatment was slightly less expensive in patients with short survival.

In a study from Kiel, Germany, Schniewind et al reported on 45 of 123 patients with malignant pleural effusions treated with TP who completed quality of life EORTC (European Organisation for Research and Treatment of Cancer) QLC C-30 questionnaires before and after treatment. The authors reported that patients experienced statistically and clinically significant improvements in functional scales throughout the study period, and noted that global health values increased after surgery throughout the entire study period. They also noted “a clear decline in dyspnea upon discharge, followed by a continuous remote increase throughout subsequent months.” The authors conclude that pleurodesis reduces respiratory symptoms. Median survival in the patients who completed the questionnaire was 10.2 months vs 7.5 months in patients who did not participate. Basso et al, from Pordenone, Italy, studied 46 patients with malignant pleural effusion treated with thoracoscopic TP (56% secondary to lung cancer). Chest tube drainage time averaged 9 days. In-hospital mortality was 8%. Following pleurodesis, there was improvement in both Karnofsky scores (4.2 to 2.7) and MRC (Medical Research Council, UK) scores (62 to 71). The authors concluded that quality of life improved following thoracoscopic TP.

Sabur et al, from Calgary, Alberta, reported upon utilization of tunneled pleural catheters in 82 patients with malignant pleural effusions studied using EORTC QLQ-C30 and LC13 quality of life scores at baseline, then at 2 and 14 weeks after catheter placement. Dyspnea improved at 2 weeks (LC13, 64 to 44; C30, 79 to 47; MRC scores, 4.2 to 3) and improvement was maintained at 14 weeks in survivors (55%).

Boshuizen, from Amsterdam, The Netherlands, did a cost analysis based upon direct analysis of data from a prospectively collected database. They report that mean costs for intrapleural catheter use were €2,173, which they noted is acceptable when compared with estimated hospitalization costs for pleurodesis.

Summary

Treatment of malignant pleural effusion with either talc pleurodesis or indwelling pleural catheters produces approximately equal results in terms of survival, control of recurrent effusion, improvement in quality of life, and cost-effectiveness. The major advantage of tunneled pleural catheters is a shorter time of hospitalization, which is counterbalanced by patient inconvenience in draining effusions. Although there may be a small cost-effectiveness benefit for pleurodesis in patients with prolonged survival, prediction of survival is not accurate enough to select a treatment method based upon this consideration. Choice of treatment method should take patient preferences into careful consideration.

Review of a number of small, early trials of intrapleural and systemic treatment following palliative management of malignant pleural effusions with chemotherapy and/or targeted agents suggests to us that there may be improved survival in patients with malignant pleural effusions treated with systemic and/or intrapleural therapy with chemotherapeutic or targeted molecular agents. Further investigations in this area are needed to confirm this impression.

Pericardial Effusion

Pericardial effusion develops in 5% to 15% of patients with cancer and is sometimes the initial manifestation of malignancy. Most pericardial effusions in cancer patients result from obstruction of the lymphatic drainage of the heart secondary to metastases. The typical presentation is that of a patient with known cancer who is found to have a large pericardial effusion without signs of inflammation. Bloody pericardial fluid is not a reliable sign of malignant effusion.

The most common malignant causes of pericardial effusions are lung and breast cancers, leukemias (specifically acute myelogenous, lymphoblastic, and chronic myelogenous leukemia [blast crisis]), and lymphomas. In one report from Kühn et al, at Children’s Hospital Boston, 39% of children with moderate to large pericardial effusions had malignant effusions.

Not all pericardial effusions associated with cancer are malignant, and cases with negative cytology may represent as many as half of cancer-associated pericardial effusions. Many effusions that initially have negative cytology will become positive over time. Such effusions are more common in patients with mediastinal lymphoma, Hodgkin lymphoma, or breast cancer. Other nonmalignant causes include drug-induced (eg, sirolimus [Rapamune] or docetaxel) or postirradiation pericarditis, tuberculosis, collagen diseases, uremia, and congestive heart failure. As reported by Fukada and colleagues, pericardial effusions can be seen in up to 35% of patients after chemoradiotherapy for esophageal cancer, but only 8% of patients will develop symptoms.

Tamponade occurs when fluid accumulates faster than the pericardium can stretch. Compression of all four heart chambers ensues, with tachycardia and diminishing cardiac output. Fluid loading can counteract intrapericardial pressure temporarily. Reciprocal filling of right- and left-sided chambers with inspiration and expiration, secondary to paradoxical movement of the ventricular septum, is a final mechanism to maintain blood flow before death.

Diagnosis

A high index of suspicion is required to make the diagnosis of pericardial effusion.

Signs and symptoms

Dyspnea is the most common symptom, but it is very nonspecific. Patients may also complain of chest pain or discomfort, easy fatigability, cough, and orthopnea, or they may be completely asymptomatic. Signs include distant heart sounds, and pericardial friction rub. With cardiac tamponade, progressive heart failure occurs, with increased shortness of breath, cold sweats, confusion, hypotension, jugular venous distention, and pulsus paradoxus. Pulsus paradoxus is often misunderstood as a “paradoxical” decrease in systolic blood pressure with inspiration. In fact, decrease in systolic blood pressure is a normal physiologic phenomenon with inspiration but is typically less than 10 mm Hg. If pulsus paradoxus is greater than 13 mm Hg, pericardial effusion should be suspected.

Chest x-ray

Chest radiographic evidence of pericardial effusion includes cardiomegaly with a “water bottle” heart; an irregular, nodular contour of the cardiac shadow; and mediastinal widening.

Electrocardiogram

ECG shows nonspecific ST- and T-wave changes, tachycardia, low QRS voltage, electrical alternans, and atrial dysrhythmia.

Pericardiocentesis and echocardiography

An echocardiogram not only can confirm a suspected pericardial effusion but also can document the size of the effusion and its effect on ventricular function. Vignon reported on the accuracy of echocardiography performed by noncardiologist residents with limited training in an ICU and concluded that brief and limited training of noncardiologist ICU residents with no prior training in ultrasound methods appears “feasible and efficient” to address simple clinical questions about using echocardiography and was specifically useful in the diagnosis of pleural and pericardial effusions. A pericardial tap with cytologic examination (positive in 50% to 85% of cases with associated malignancy) will confirm the diagnosis of malignant effusion or differentiate it from other causes of pericardial effusion. Serious complications, including cardiac perforation and death, can occur during pericardiocentesis, even when performed with echocardiographic guidance by experienced clinicians.

Tumor markers/staining and cytogenetics

Tumor markers or special staining and cytogenetic techniques may improve the diagnostic yield, but ultimately an open pericardial biopsy may be necessary. Szturmowicz et al, from Warsaw, Poland, studied pericardial fluid carcinoembryonic antigen (CEA) and cytokeratin fragment (CYFRA) 21-1 levels in 84 patients with pericardial effusion. There were significant differences in patients with malignant vs benign effusions with both tests. With cutoff points of > 100 ng/mL for CYFRA 21-1 and > 5 ng/mL for CEA, 14 of 15 patients who had malignant pericardial effusion with negative cytologic results had a positive result on one or both tests.

CT and MRI

CT and MRI as diagnostic adjuncts may provide additional information about the presence and location of loculations or mass lesions within the pericardium and adjacent structures. Restrepo et al have published a comprehensive, well-illustrated description of CT features of pericardial tamponade.

Cardiac catheterization

This may occasionally be of value to rule out superior vena caval obstruction, diagnose microvascular tumor spread in the lungs with secondary pulmonary hypertension, and document constrictive pericarditis before surgical intervention. Right atrial and pulmonary capillary wedge pressures may also be measured. In most cases of effusion, catheterization does not yield information beyond the echocardiogram.

Pericardioscopy

This allows visualization and biopsy at the time of subxiphoid or thoracoscopic pericardiotomy and can improve the diagnostic yield.

Prognosis

In general, cancer patients who develop a significant pericardial effusion have a high mortality, with a mean time to death of 2.2 to 4.7 months. However, about 25% of selected patients treated surgically for cardiac tamponade enjoy a 1-year survival.

Investigators in Barcelona, Spain studied the effects of volume expansion in patients with large pericardial effusions and pericardial tamponade. They administered 500 mL of normal saline over 10 minutes and measured hemodynamic and echocardiographic parameters. A total of 57% had tamponade on physical examination, and 20% were hypotensive. Volume expansion resulted in increases in mean arterial, intrapericardial, right atrial, and left ventricular end-diastolic pressures. The cardiac index increased by > 10% in 47% of patients and remained unchanged in 22%, but actually decreased in 31%. No patient had clinical complications. Predictors of improved hemodynamics were a pressure below 100 mm Hg and a low cardiac index. Sagrista-Sauleda et al reported in 2008 that in approximately half of patients with cardiac tamponade, particularly those with low blood pressure, cardiac output will increase after volume overload. Therefore, the administration of fluids should be guided by the patient’s clinical status rather than used routinely in patients with suspected tamponade.

Treatment

General concepts

As is the case with malignant pleural effusion, it is difficult to evaluate treatments for pericardial effusion because of the many variables. Because malignant pericardial effusion is less common than malignant pleural effusion, it is more difficult to collect data in a prospective manner. Certain generalizations can, however, be derived from available data:

• All cancer patients with pericardial effusion require a systematic evaluation and should not be dismissed summarily as having an untreatable and/or terminal problem.

• Ultimately, both the management and natural course of the effusion depend on (1) the underlying condition of the patient, (2) the extent of clinical symptoms associated with the cardiac compression, and (3) the type and extent of the underlying malignant disease.

General treatment approaches

Asymptomatic, small effusions may be managed with careful follow-up and treatment directed against the underlying malignancy. On the other hand, cardiac tamponade is a true oncologic emergency. Immediate pericardiocentesis, under echocardiographic guidance, may be performed to relieve the patient’s symptoms. A high failure rate is anticipated because the effusion rapidly recurs unless steps are taken to prevent it. Therefore, a more definitive treatment plan should be made following the initial diagnostic/therapeutic tap.

In patients with symptomatic, moderate-to-large effusions who do not present as an emergency, therapy should be aimed at relieving symptoms and preventing recurrence of tamponade or constrictive pericardial disease. Patients with tumors responsive to chemotherapy or radiation therapy may attain longer remissions with appropriate therapy.

There are two theoretical mechanisms for control of pericardial effusion: (1) creation of a persistent defect in the pericardium, allowing fluid to drain out and be reabsorbed by surrounding tissues; or (2) sclerosis of the mesothelium, resulting in the formation of fibrous adhesions that obliterate the pericardial cavity.

Postmortem studies have demonstrated that both of these mechanisms are operative. The fact that effusions can recur implies that there is either insufficient damage to the mesothelial layer or that rapid recurrence of effusion prevents coaptation of visceral and parietal pericardium and prevents the formation of adhesions. This, in turn, would suggest that early closure of the pericardial defect can result in recurrence.

Treatment methods. Various methods can be used to treat malignant pericardial effusion.

• Observation-Observation alone may be reasonable in the presence of small asymptomatic effusions.

• Pericardiocentesis-Pericardiocentesis is useful in relieving tamponade and obtaining a diagnosis. Echocardiographic guidance considerably enhances the safety of this procedure. About 90% of pericardial effusions will recur within 3 months after pericardiocentesis alone.

• Pericardiocentesis and percutaneous tube drainage-Pericardiocentesis and percutaneous tube drainage can now be performed with low risk and are recommended by some clinical groups. Marcy et al, of Nice, France, reviewed multiple, well-illustrated percutaneous methods for management of malignant pericardial effusions. Problems that may occur include occlusion or displacement of the small-bore tubes, dysrhythmia, recurrent effusion, and infections. Mayo Clinic cardiologists recommend initial percutaneous pericardiocentesis with extended catheter drainage as their technique of choice.

Kunitoh et al, from the National Cancer Center Hospital in Tokyo, performed a randomized controlled trial in 80 patients who had undergone pericardial drainage for malignant pericardial effusion. These patients were then randomized to either observation alone (A) after drainage or intrapericardial bleomycin instillation (15 mg followed by 10 mg every 48 hours [B]). Drainage tubes were removed when daily drainage was 20 mL or less. The results, published in 2009, showed that survival with control of malignant pleural effusion at 2 months was 29% in arm A and 46% in arm B (P = .08); the median survival was 79 days vs 119 days.

• Intrapericardial sclerotherapy and chemotherapy-Intrapericardial sclerotherapy and chemotherapy following percutaneous or open drainage have been reported to be effective treatments by some groups. Problems include pain during sclerosing agent treatments and recurrence of effusions. Good results have been reported with instillation of a number of agents, including bleomycin (10 mg), cisplatin (30 mg), mitomycin (2 mg), thiotepa (1.5 mg), and mitoxantrone (10 to 20 mg). Agents are selected based on their antitumor or sclerosing effect.

Martinoni et al, from Milan, Italy, reported on the use of intrapericardial administration of thiotepa (15 mg on days 1, 3, and 5) following placement of a pericardial drainage catheter in 33 patients with malignant pericardial effusion. There were three recurrent effusions (9.1%). The median survival time was 115 days. They concluded that this protocol is safe, well tolerated, and improves the quality and duration of life.

• Pericardiocentesis and prolonged catheter drainage-Simple pericardiocentesis alone has unacceptable recurrence rates of up to 90%. However, using a guidewire, a pigtail catheter may be inserted into the pericardial space and left in place until the drainage becomes minimal. Percutaneous catheter drainage has a low complication rate, but higher rates of recurrence than pericardial window. In their experience with 246 patients, McDonald and colleagues reported a 16.5 % rate of recurrent symptomatic effusion after percutaneous catheter drainage vs 5% after pericardial window. However, for patients with malignant effusions and limited life expectancy, results may be comparable, as recently reported by Patel and others.

• Balloon pericardial window-After percutaneous placement of a guidewire following pericardiocentesis, a balloon-dilating catheter can be placed across the pericardium under fluoroscopic guidance and a window created by balloon inflation.

At the National Taiwan University, cardiologists performed percutaneous double-balloon pericardiotomy in 50 patients with cancer and pericardial effusion and followed their course using serial echocardiograms. Success without recurrence was achieved in 88%. Fifty percent of patients died within 4 months, and 25% survived to 11 months.

Sidebar:Ruiz-García et al, from Madrid, Spain, treated 16 patients with malignant pericardial effusions, using percutaneous balloon pericardiotomy as the initial and definitive treatment. All patients had been hemodynamically compromised on echocardiography. There were no acute complications and all cases were initially successful. There were three later failures, requiring two pericardial window surgeries and one repeat percutaneous balloon pericardiotomy. The authors consider percutaneous balloon pericardiotomy to be a simple, safe technique that can be effective in preventing recurrence in many patients with severe malignant pericardial effusion (Ruiz-García J et al: Rev Esp Cardiol 66:357–363, 2013).

• Subtotal pericardial resection-Subtotal pericardial resection is seldom performed today. Although it is the definitive treatment, in that there is almost no chance of recurrence or constriction, higher morbidity and longer recovery time render this operation undesirable in patients who have a short anticipated survival time. Its use is restricted to patients with good prognosis and constrictive pericarditis rather than pericardial effusion.

• Limited pericardial resection-Limited pericardial resection (pericardial window) via anterior thoracotomy, thoracoscopic, or subxiphoid approach has a low morbidity. There is a low risk of recurrence. Cardiac herniation is possible if the size of the opening in the pericardium is not carefully controlled. A pericardial drain is typically placed at the time of the procedure. If necessary, a sclerosing agent may also be administered. Subxiphoid pericardial window may be performed with the under local anesthesia or combined with endoscopic instrumentation.

At City of Hope, Cullinane et al reported on 62 patients with malignant disease who had a surgical pericardial window created for management of pericardial effusion. Windows were created either thoracoscopically (32) or by subxiphoid (12) or limited thoracotomy (18) approaches. Primary tumors included NSCLC, breast, hematologic, and other solid-organ malignancies. Three recurrent effusions (4.8%) required reoperations. Eight patients (13%) died during the same admission as their surgical procedure. The median survival was much shorter for patients with NSCLC (2.6 months) than for patients with breast cancer (11 months) or hematologic malignancy (10 months). The surgical pericardial window is a safe and durable operative procedure that may provide extended survival in certain subgroups of cancer patients.

• Development of a subxiphoid pericardioperitoneal window-Development of a subxiphoid pericardioperitoneal window through the fused portion of the diaphragm and pericardium allows continued drainage of pericardial fluid into the peritoneum. This may be done laparoscopically in stable patients, but we advise caution. As described in a case series by Romano and Glass, carbon dioxide pneumoperitoneum may adversely affect the cardiopulmonary hemodynamics due to increased intra-abdominal pressure, caval compression, and decreased venous return. There will also be increased afterload. In addition, there is the potential for prolonged hypercarbia, acidosis, and hypoxemia.

Toth et al, from Miskolc, Hungary, reported in 2012 on a new technical method using a Chamberlain, parasternal mediastinoscopic approach to create a pericardial window in 22 patients with malignant pericardial effusions. There were no operative deaths, and one patient (4.5%) experienced recurrence of a pericardial effusion.

• Technical factors-Prior pleurodesis for malignant pleural effusion makes an ipsilateral transpleural operation difficult or impossible. In lung cancer patients, major airway obstruction may preclude single-lung anesthesia and, thus, thoracoscopic pericardiectomy. Prior median sternotomy may prohibit the use of a subxiphoid approach.

• Complications-A 30-day mortality rate of 10% or higher has been reported for all of these modalities but is related more to the gravity of the underlying tumor and its sequelae. A small percentage of patients will develop severe problems with pulmonary edema or cardiogenic shock following pericardial decompression. The mechanisms of these problems are poorly understood.

Wagner et al, from Memorial Sloan-Kettering Cancer Center, retrospectively studied 179 consecutive pericardial windows for malignant effusions over a 5-year period. These included lung (44%), breast (20%), hematologic (10%), and gastrointestinal cancers (7%). The overall survival of the whole group was poor, with a median of 5 months survival. They defined paradoxical hemodynamic instability (PHI) as hypotension and shock in the immediate postoperative period. PHI occurred in 19 (11%) of patients. Patients most likely to have PHI showed evidence of tamponade on echocardiogram (89% vs 56% without tamponade; P = .005), had a positive cytology or pathology (68% vs 41%; P = .03), and had larger volumes drained. Most important, 58% of patients with paradoxical hemodynamic instability did not survive the initial hospitalization.

Late neoplastic pericardial constriction can occur following initially successful partial pericardiectomy. Patients with combined malignant pericardial and pleural effusions will often have relief of recurrent pleural effusion following control of pericardial effusion, perhaps because reducing systemic venous pressure results in reduced production of pleural fluid. Simultaneous pleurodesis in the left side of the chest following a pericardial window procedure might increase the incidence of recurrent pericardial effusion and should be avoided.

• Radiotherapy-External-beam irradiation is utilized infrequently in this clinical setting but may be an important option in specialized circumstances, especially in patients with radiosensitive tumors who have not received prior radiation therapy. Responses ranging from 66% to 93% have been reported with this form of treatment, depending on the type of associated tumor.

• Chemotherapy-Systemic chemotherapy is effective in treating pericardial effusions in patients with lymphomas, hematologic malignancies, or breast cancer. Long-term survival can be attained in these patients. If the pericardial effusion is small and/or asymptomatic, invasive treatment may be omitted in some of these cases. Data are limited regarding the effectiveness of systemic chemotherapy or chemotherapy delivered locally in prevention of recurrent pericardial and pleural effusion. Several studies have reported on the effectiveness of intrapericardial instillation of chemotherapy (most commonly cisplatin) for the treatment of malignant effusion. It is unclear whether the results are due to cytotoxic effect on malignant cells or the sclerosing effect of the drugs.

Biologic therapy with various agents is in the early stages of investigation.

Malignant Ascites

Malignant ascites results when there is an imbalance in the secretion of proteins and cells into the peritoneal cavity and absorption of fluids via the lymphatic system. Greater capillary permeability as a result of the release of cytokines by malignant cells increases the protein concentration in the peritoneal fluid. Recently, several studies have demonstrated higher levels of VEGF, a cytokine known to cause capillary leak, in the sera and effusions of patients with malignancies.

Signs and Symptoms

Patients with malignant ascites usually present with anorexia, nausea, respiratory compromise, and immobility. Complaints of abdominal bloating, heaviness, and ill-fitting clothes are common. Weight gain despite muscle wasting is a prominent sign.

Diagnosis

A malignant etiology accounts for only 10% of all cases of ascites. Nonmalignant diseases causing ascites include liver failure, congestive heart failure, and occlusion of the inferior vena cava or hepatic vein. About one-third of all patients with malignancies will develop ascites. Malignant ascites has been described with many tumor types but is most commonly seen with gynecologic neoplasms (~50%), gastrointestinal malignancies (20% to 25%), and breast cancer (10% to 18%). In 15% to 30% of patients, the ascites is associated with diffuse carcinomatosis of the peritoneal cavity.

Physical examination

Physical examination does not distinguish whether ascites is due to malignant or benign conditions. Patients may have abdominal fullness with fluid wave, anterior distribution of the normal abdominal tympany, and pedal edema. Occasionally, the hepatic metastases or tumor nodules studding the peritoneal surface can be palpated through the abdominal wall, which has been altered by ascitic distention.

Radiologic studies

Radiographs. Ascites can be inferred from plain radiographs of the abdomen. Signs include a ground-glass pattern and centralization of the intestines and abdominal contents.

Ultrasonography. Abdominal ultrasonography has been shown to be the most sensitive, most specific method for detecting and quantifying ascites. It also permits delineation of areas of loculation.

Success at removing peritoneal fluid in patients was markedly better with ultrasonographic assistance, as demonstrated in a randomized trial by Nazeer et al. Ultrasonography improved the physicians’ ability to aspirate ascites from 67% (27 of 44 patients) to 95% (40 of 42 patients).

CT. Abdominal and pelvic CT is effective in detecting ascites. In addition, CT scans may demonstrate masses, mesenteric stranding, omental studding, and diffuse carcinomatosis. Use of IV and oral contrast agents is necessary, thus increasing the degree of invasiveness of this modality.

Paracentesis. After the diagnosis of peritoneal ascites has been made on the basis of the physical examination and imaging, paracentesis should be performed to characterize the fluid. The color and nature of the fluid often suggest the diagnosis. Malignant ascites can be bloody, opaque, chylous, or serous. Benign ascites is usually serous and clear.

Analysis of the fluid should include cell count, cytology, LDH level, proteins, and appropriate evaluation for infectious etiologies. In addition, the fluid can be sent for the determination of tumor markers, such as CEA, CA-125, p53, and human chorionic gonadotropin-β (hCG-β). The hCG-β level is frequently elevated in malignancy-related ascites and has been combined with cytology to yield an 89.5% efficiency in diagnosis. The use of DNA ploidy indices, Decker et al found, allowed a 98.5% sensitivity and a 100% sensitivity in the identification of malignant cells within ascitic fluid. The use of the telomerase assay, along with cytologic evaluation of the ascitic fluid contents, Li et al reported, has a 77% sensitivity in detecting malignant ascites.

Laparoscopy. Several studies have utilized minimally invasive laparoscopy as the diagnostic tool of choice. The fluid can be drained under direct visualization, the peritoneal cavity can be evaluated carefully, and any suspicious masses can be biopsied at the time of the laparoscopy.

Prognosis

The presence of ascites in a patient with malignancy often portends end-stage disease. The median survival after the diagnosis of malignant ascites ranges from 7 to 13 weeks. Patients with gynecologic and breast malignancies have a better overall prognosis than patients with gastrointestinal malignancies.

Treatment

Medical therapy

Traditionally, the first line of treatment is medical management. Medical therapies include repeated paracentesis, fluid restriction, diuretics, chemotherapy, and intraperitoneal sclerosis.

Repeated paracentesis

Repeated paracentesis, probably the most frequently employed treatment modality, provides significant symptomatic relief in the majority of cases. The procedure is minimally invasive and can be combined with abdominal ultrasonography to better localize fluid collections. High-volume paracentesis has been performed without inducing significant hemodynamic instability and with good patient tolerance.

After paracentesis, 78% of all patients reported relief of their symptoms, especially in the areas of abdominal bloating, anorexia, dyspnea, insomnia, and fatigue. In addition, overall quality of life improved after paracentesis.

Significant morbidity occurs with repeated taps and becomes more severe with each tap necessary to alleviate symptoms. Ascitic fluid contains a high concentration of proteins. Routine removal of ascites further depletes protein stores. The removal of large volumes of fluid also can result in electrolyte abnormalities and hypovolemia. In addition, complications can result from the procedure itself. They include hemorrhage, injury to intra-abdominal structures, peritonitis, and bowel obstruction. Contraindications to repeated paracentesis are viscous loculated fluid and hemorrhagic fluid.

With the placement of an intraperitoneal port, used also for the instillation of intraperitoneal chemotherapy, removal of ascitic fluid is possible without the need for repeated paracentesis. Other possible catheters for use in repeated paracentesis include PleurX and Tenckoff catheters (used for intraperitoneal dialysis). Placement of a semipermanent catheter minimizes the risk of injury to intra-abdominal structures. However, the benefits are tempered by increased infectious risks as well as the possibility of a nonfunctioning catheter requiring removal and replacement.

An analysis of the efficacy and cost-effectiveness of PleurX catheter drainage in treatment-resistant, recurrent malignant ascites was performed in the United Kingdom for the National Institute for Health and Care Excellence. The study, reported in 2012 by White and Carolan-Rees, concluded that use of the PleurX catheter in this population was clinically effective, with low complication rates. In addition, the use of PleurX was associated with improved quality of life and decreased overall cost when compared with serial paracentesis.

Diuretics and restriction of fluid and salt. Unlike ascites from benign causes such as cirrhosis and congestive heart failure, malignant ascites responds poorly to fluid restriction, decreased salt intake, and diuretic therapy. The most commonly used diuretics (in patients who may have some response to diuretic treatment) are spironolactone (Aldactone) and amiloride (Midamor). Patients with massive hepatic metastases are most likely to benefit from spironolactone.

The onset of action for spironolactone is delayed (3–4 days), whereas the effects of amiloride are seen after 24 hours. The most common complications associated with these diuretics are painful gynecomastia, renal tubular acidosis, and hyperkalemia.

Chemotherapy. Chemotherapy, both systemic and intraperitoneal, has had some success in the treatment of malignant ascites. The most commonly used agents are cisplatin and mitomycin. Intraperitoneal hyperthermic chemotherapy has been used with some efficacy in gastrointestinal malignancies to decrease recurrence of ascites as well as to prevent the formation of ascites in patients with peritoneal carcinomatosis.

Sclerotherapy. Sclerosing agents include bleomycin (60 mg/50 mL of normal saline) and talc (5 g/50 mL of normal saline). Responses are seen in ~30% of patients treated with these agents.

Theoretically, intraperitoneal chemotherapy and sclerosis obliterate the peritoneal space and prevent future fluid accumulation. If sclerosis is unsuccessful, it may produce loculations and make subsequent paracentesis difficult.

Other therapies. Approved for use to treat malignant ascites in the European Union since 2009, catumaxomab (Removab) is a trifunctional antibody specific for epithelial cell adhesion molecule (EPCAM) on tumor cells, CD3 antigen on T cells, and the Fc regions on accessory cells such as macrophages, dendritic cells, and natural killer cells. A phase II/III clinical trial demonstrated efficacy of the antibody, given as intraperitoneal infusions, in decreasing the number of and timing between paracentesis sessions needed to control the volume and symptoms of malignant ascites.

Catumaxomab is being studied in a randomized phase IIIb trial to improve on the dosing regimen of the antibody in patients with EPCAM+ epithelial carcinomas. The study is ongoing and results are pending.

Experimental models and early clinical trials have shown that an intraperitoneal bolus of tumor necrosis factor (45–350 μg/m2) given weekly may be effective in resolving malignant ascites. Other cytokines, including interferon-α, have had various degrees of success. A randomized, prospective trial definitively addressing the role of cytokines and other biologic treatments in the management of malignant ascites has yet to be completed. Intraperitoneal injection of antibodies directed at VEGF has shown promise in decreasing ascites in early-phase clinical trials, but further studies are needed.

Aflibercept (Zaltrap) has demonstrated the ability to reduce formation of ascites in preclinical models of epithelial ovarian cancer (EOC), as well as in patients with advanced EOC. Aflibercept, a potent angiogenesis inhibitor fusion protein, comprises portions of human VEGF receptor R1+R2 (Flt-1, KDR) extracellular domains fused to the Fc-portion of human IgG. Aflibercept binds VEGF-A and neutralizes all VEGF-A isoforms plus placental growth factor.

A randomized, phase II study by Gotlieb et al determined the efficacy of intravenous aflibercept in the management of symptomatic malignant ascites from ovarian cancer. A total of 26 patients received placebo and 29 patients were treated. Mean time to paracentesis was longer in the aflibercept arm (55.1 days) than in the placebo arm (23.3 days). Side effects included dypsnea, fatigue, dehydration, and bowel perforation.

Surgical techniques

Limited surgical options are available to treat patients who have refractory ascites after maximal medical management, demonstrate a significant decrease in quality of life as a result of ascites, and have a life expectancy of > 3 months.

Peritoneovenous shunts. These have been used since 1974 for the relief of ascites associated with benign conditions. In the 1980s, shunting was applied to the treatment of malignant ascites.

The LeVeen shunt contains a disc valve in a firm polypropylene casing, whereas the Denver shunt has a valve that lies within a fluid-filled, compressible silicone chamber. Both valves provide a connection between the peritoneal cavity and venous system that permits the free flow of fluid from the peritoneal cavity when a 2- to 4-cm water pressure gradient exists.

Success rates vary with shunting, depending on the nature of the ascites and the pathology of the primary tumor. Patients with ovarian cancer, for example, do very well, with palliation achieved in ≥ 50% of cases. However, ascites arising from gastrointestinal malignancies is associated with a poorer response rate (10% to 15%).

Candidates for shunt placement should be carefully selected. Cardiac and respiratory evaluations should be performed prior to the procedure. Shunt placement is contraindicated in the presence of the following:

• a moribund patient whose death is anticipated within weeks

• peritonitis

• major organ failure

• adhesive loculation

• thick, tenacious fluid.

Complications of shunting. Initial concerns about the use of a shunt in the treatment of malignant ascites centered on intravascular dissemination of tumor. In practice, there has been little difference in overall mortality in patients with and without shunts.

Disseminated intravascular coagulation. During the early experience with shunting, particularly in cirrhotic patients, symptomatic clinical disseminated intravascular coagulation (DIC) developed rapidly and was a major source of morbidity and mortality. However, overwhelming DIC occurs infrequently in the oncologic population.

The pathophysiology of DIC has been studied extensively and is thought to be multifactorial. The reinfusion of large volumes of ascitic fluid may cause a deficiency in endogenous circulating coagulation factors by dilution. Secondarily, a fibrinolytic state is initiated by the introduction of soluble collagen (contained within the ascitic fluid) into the bloodstream, leading to a DIC state. Infrequently, full-blown DIC is the result and requires ligation of the shunt or even shunt removal. Discarding 50% to 70% of the ascitic fluid before establishing the peritoneovenous connection may prevent this complication but may increase the risk of early failure due to a reduced initial flow rate.

Commonly, coagulation parameters are abnormal without signs or symptoms. In some institutions, these laboratory values are so consistently abnormal that they are used to monitor shunt patency. Abnormalities most commonly seen include decreased platelets and fibrinogen and elevated prothrombin time, partial thromboplastin time, and fibrin split products.

Other common complications include shunt occlusion (10%–20%), heart failure (6%), ascitic leak from the insertion site (4%), infection (< 5%), and perioperative death (10% to 20% when all operative candidates are included).

Shunt patency may be indirectly correlated with the presence of malignant cells. One study found that patients with positive cytology results had a 26-day shunt survival, as compared with 140 days in patients with negative cytology results. Other studies have failed to demonstrate a correlation between ascites with malignant cells and decreased survival.

Clearly, shunting is not a benign procedure, but in carefully selected patients who have not responded to other treatment modalities and who are experiencing symptoms from ascites, it may provide needed palliation. Because of the limited effectiveness of peritoneovenous shunts, patients should be carefully selected prior to shunt placement.

Radical peritonectomy. Other surgical procedures used to treat malignant ascites have been proposed. They include radical peritonectomy combined with intraperitoneal chemotherapy. This is an extensive operation with significant morbidity, although initial results appear to demonstrate that it decreases the production of ascites. To date, no randomized trial has demonstrated that radical peritonectomy increases efficacy or survival. However, there is an emerging body of literature supporting use of intraperitoneal chemotherapy in the management of malignant ascites. Although different chemotherapeutic agents have been studied for intraperitoneal use, Mitomycin-C is most often used.

Combined fluid complications. Combinations of pleural and pericardial effusion, ascites and pleural effusion, or even ascites combined with pleural and bilateral pleural effusion are not uncommon. Management is complex in these cases, and in the authors’ experience, survival is more limited.

Management of patients with ovarian cancer, ascites, and pleural effusion is particularly challenging. Two reports published in 2010 are illustrative.

Kim et al, from Seoul National University College of Medicine, Korea, studied 38 patients with ovarian cancer with pleural effusion on CT scan who had undergone thoracentesis before treatment. The investigators assessed the amount of ascites and pleural effusion, as well as lymph node enlargement and presence of pleural nodules or thickening. A total of 16 patients (42%) had a malignant pleural effusion. In patients with malignant pleural effusion, the volumes of pleural effusions were larger than in those with nonmalignant effusions. Pleural nodules were found more frequently in the malignant group (50% vs 0%). Supradiaphragmatic lymph node enlargement also was more frequent in the malignant group (25% vs 9%). The investigators concluded that the probability of malignant pleural effusion was correlated with the volume of pleural effusion, the presence of pleural nodules, and supradiaphragmatic lymph node enlargement on CT.

Diaz et al, from Memorial Sloan Kettering Cancer Center, performed VATS of pleural effusions in patients with advanced ovarian cancer. They studied 42 patients with a median age of 58 years and a median CEA-125 of 1,747 units/mL. Effusions were right-sided in 30 patients (71%). Macroscopic pleural disease was found in 29 (69%) of patients. Of 11 patients with negative cytology, macroscopic pleural disease was found in 4 (36%). Six of 18 patients had intrathoracic cytoreductive surgery after VATS. A total of 29 of 42 patients (69%) underwent attempted primary abdominal surgical debulking. VATS investigation prompted changes in management in 43% of cases.

Suggested Reading

On Malignant Pleural Effusion

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On Pericardial Effusion

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On Malignant Ascites

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